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Procaine inhibits the proliferation and DNA methylation in human hepatoma cells

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Abstract

Purpose

Transcriptional silencing of tumor suppressor genes associated with DNA hypermethylation has been known as a hallmark of human cancer. In this study, we revealed that a local anesthetic, procaine (PCA), possessed growth-inhibitory and demethylating effect on human hepatoma cells in vitro and in vivo.

Methods

The viability of PCA-treated cells with or without trichostatin A (TSA) was investigated. To clarify the mechanism of the antiproliferating effect of PCA, TUNEL assay, FACS analysis, and morphological observation of PCA-treated cells were performed. The expression levels and epigenetic alterations of 4 genes inactivated by DNA hypermethylation in hepatocellular carcinoma (HCC) were examined in hepatoma cells with or without PCA treatment. The growth-inhibitory and demethylating effect of PCA in vivo was tested in nude mice bearing xenograft.

Results

The viability of HLE, HuH7, and HuH6 cells was significantly decreased by PCA treatment. In these cells, the combination treatment with TSA and PCA exhibited stronger reduction of the viability. Inhibition of S/G2/M transition, morphological changes such as vacuolation and no increase in apoptosis rate were observed in the PCA-treated HLE cells. All the genes transcriptionally suppressed by DNA hypermethylation were demethylated and reactivated with PCA treatment. PCA treatment led to partial demethylation and significant reduction in tumor volume in vivo.

Conclusions

These data indicated that PCA had growth-inhibitory and demethylating effects on human hepatoma cells in vitro and in vivo. PCA may be a candidate agent for future therapies for HCC.

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Authors and Affiliations

  1. Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, 260-8670, Japan

    Motohisa Tada, Fumio Imazeki, Kenichi Fukai, Makoto Arai, Rintarou Mikata & Osamu Yokosuka

  2. Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan

    Akemi Sakamoto & Takeshi Tokuhisa

Authors
  1. Motohisa Tada
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  2. Fumio Imazeki
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  3. Kenichi Fukai
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  4. Akemi Sakamoto
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  5. Makoto Arai
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  6. Rintarou Mikata
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  7. Takeshi Tokuhisa
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  8. Osamu Yokosuka
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Correspondence to Osamu Yokosuka.

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Tada, M., Imazeki, F., Fukai, K. et al. Procaine inhibits the proliferation and DNA methylation in human hepatoma cells. Hepatol Int 1, 355–364 (2007). https://doi.org/10.1007/s12072-007-9014-5

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  • DOI: https://doi.org/10.1007/s12072-007-9014-5

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